atovaquone

P1, N=18, Recruiting, Emory University | Initiation date: Oct 2024 --> Jan 2025

The obtained findings exhibited the high in vitro potency of QBA, especially in combination with atovaquone against T. gondii RH strain tachyzoites. Although apoptosis induction can be suggested as one of the principle mechanisms, more studies are required to elucidate its accurate mechanisms, as well as its efficacy and safety in animal models and clinical settings.

To address this matter, an O2 regulator (SNP@Ato) is designed for breaking chemoresistance and enhancing PDT, which is constructed by loading Atovaquone (Ato) through self-assembly and host-guest interaction between β-cyclodextrin functionalized tetraphenylporphyrin (TPP-CD4) and thioketal-linked camptothecin/azobenzene (Azo-TK-CPT)...Compared with the SNP group without oxygen-regulator, SNP@Ato exhibits a remarkable improvement of the therapeutic effect against hypoxic tumors in vitro and in vivo. This work proposes a novel paradigm for overcoming hypoxia-induced therapeutic resistance.

P1, N=18, Recruiting, Emory University

Using the approved antiprotozoal drug and STAT3 inhibitor Atovaquone (Ato) as prototype for a hydrophobic small molecule, we show that Ato-loaded ovalbumin-coated nanocapsules (Ato-nCap) preferentially enter human myeloid cells...By measuring the effect of Ato nanocarriers on induced STAT3 phosphorylation in IL-10-primed human dendritic cells and constitutive STAT3 phosphorylation in human melanoma cells, we demonstrate that the intracellular Ato release is particularly effective from Ato nanocrystals and less toxic than equal doses of free drug. These new nanocarriers thus represent effective systems for intracellular drug delivery.

The patient, initially treated with trimethoprim-sulfamethoxazole, was switched to atovaquone due to gastrointestinal intolerance. This case highlights the importance of recognising atypical PJP presentations causing granulomatous disease in immunosuppressed patients. While rare, documenting such cases may improve diagnosis using less invasive methods and help determine optimal treatment durations for resolution of these atypical infections.

P2, N=28, Recruiting, Emory University | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O2 conservation...Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO2@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both in vitro and in vivo. Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO2@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.

Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

P2, N=28, Recruiting, Emory University | Not yet recruiting --> Recruiting

This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.

The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.

Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.

P1, N=21, Completed, University of Oxford | Active, not recruiting --> Completed | Trial primary completion date: Jun 2023 --> Oct 2023

Homeostasis was successfully achieved with epinephrine and endoscopic clipping...Infectious disease and Oncology were consulted and he was started on Biktarvy and liposomal doxorubicin. He was also started on Benzathine penicillin G for syphilis, Atovaquone and azithromycin for opportunistic infection prophylaxis... With advancements in HIV treatment, early diagnosis of gastrointestinal KS can prevent severe complications including hemorrhagic shock and patients can have a favorable outcome. Further interventions are needed to assess the rates of underdiagnosed GI KS along with probable implementation of screening endoscopies.

Atovaquone (Ato, a mitochondrial-respiration inhibitor) and cabozantinib (cabo, a MDSCs eliminator) were concurrently released in response to the intratumorally overexpressed HO...Taken together, we developed a transdermal and intravenous dual-administration paradigm, which effectively reversed the hypoxic and immunosuppressive tumor microenvironment in the treatment of the malignant melanoma. We believe our study will open a new path for the effective elimination of the primary tumors and the real-time control of tumor metastasis.

Active compound clusters frequently contain α/β-unsaturated carbonyl groups, which are also observed in both endogenous quinone electron carriers and atovaquone–a potent inhibitor of OXPHOS. Treatment with oryzalin, allylestrenol, esbiothrin, and lacidipine decreased basal respiration rates and ATP production in ID-8 cells. Thus, 4 of 6 compound classes prioritized by the pipeline show inhibitory effects against ovarian cancer cells.

To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine.

P1, N=21, Active, not recruiting, University of Oxford | Trial primary completion date: Mar 2023 --> Jun 2023

However, studies looking at the combination of immunotherapies with carboplatin and paclitaxel, which are the mainstay chemotherapies for EOC, have not improved progression-free survival rates. We are also monitoring transcriptomic responses of EOC cells treated with atovaquone to identify changes in expression of DAMPs and other immune-activating pathways through RNA sequencing. Our ultimate goal is to test T cell recognition and responses toward atovaquone-treated EOC cells with the intention of utilizing this chemotherapeutic agent as an adjunct to immunotherapeutic efforts for EOC.

This research demonstrates the involvement of the MSN in doxorubicin resistance through IL-6/MSN/STAT3 pathway and provides a novel therapeutic candidate for TNBC patients.

P1, N=21, Active, not recruiting, University of Oxford | Recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Aug 2023 | Trial primary completion date: Dec 2022 --> Mar 2023

She has been on adalimumab and azathioprine since 2015 with no recent flare ups; her last dose of adalimumab was given just before this admission...Given concern for sepsis in the setting of pregnancy, she was admitted to ICU and started on vancomycin and ampicillin-sulbactam for broad coverage...Antibiotics were broadened to vancomycin, meropenem, clindamycin, micafungin, azithromycin and pentamidine without meaningful clinical improvement...Final pathology revealed ALK-positive anaplastic large-cell lymphoma, a type of non-Hodgkin lymphoma, and the patient was started on chemotherapy with cyclophosphamide and doxorubicin...Antibiotics were discontinued, except atovaquone for PCP prophylaxis, and the patient was discharged on hospital day 26.It is hypothesized that T cell dysfunction is involved in the pathogenesis of Crohn’s disease and studies have reported that patients with chronic inflammatory disorders might have an increased baseline risk of lymphomas regardless of TNF antagonist treatments...Some lymphomas cause inflammatory responses that respond to chemotherapy. This case emphasizes the importance of avoiding singular focus on opportunistic infection in IBD patients.

Atovaquone effectively inhibits cell proliferation and induces cell cycle arrest and apoptosis by suppression of STAT3 signaling pathway in Raji cells. It can be a potential therapeutic agent against non-Hodgkin's lymphoma.

Using this approach, we identified atovaquone as a STAT3 inhibitor and disulfiram as a BCL6 inhibitor. These findings suggest that inhibition of oncogenic transcription factors like STAT3 and BCL6, in conjunction with novel immune-targeted therapeutics like PD1-IL2v, have the potential for long term disease control in lymphomas. This research collaboration was supported through the imCORE network.

Here, a phototherapeutic nanococktail atovaquone/17-dimethylaminoethylamino-17-demethoxygeldanamycin/glyco-BODIPY (ADB) was developed to enhance photodynamic therapy (PDT) and photothermal therapy (PTT) via alleviation of hypoxia and thermal resistance that was constructed using supramolecular self-assembly of glyco-BODIPY (BODIPY-SS-LAC, BSL-1), hypoxia reliever atovaquone (ATO), and heat shock protein inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG)...Moreover, ADB exhibited good biosafety, and tumor eradication in vivo. Hence, this as-developed phototherapeutic nanococktail overcomes the substantial obstacles encountered by phototherapy in tumor treatment and offers a promising approach for the eradication of tumors.

Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.

DHODH inhibitor suppressed DHODH-mediated ROS generation and HIF1A upregulation. Targeting DHODH using clinically available inhibitor, atovaquone, might provide a new strategy to treat OTSCC.

Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform...Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.

All participants received a 3-day cycle of lymphodepleting chemotherapy with fludarabine and cyclophosphamide 5 days prior to infusion and ide-cel was administered at target doses of 150×10 6 to 450×10 6 CAR-positive T cells. All patients but one received antiviral prophylaxis with val/acyclovir or famciclovir. Seventeen patients received pneumocystis prophylaxis with atovaquone or trimethoprim-sulfamethoxazole. Only 2 patients received antibacterial prophylaxis with levofloxacin and no patients received antifungal prophylaxis...Following infusion of cells, 24 patients (89%) developed CRS with 54% of those receiving ≥ 1 dose of tocilizumab and 17% receiving ≥ 1 dose of corticosteroid... Our study in this cohort of patients provides clarity on specific infectious complications in a unique population, and is of particular relevance given the recent FDA approval of ide-cel. Of note, these results represent a cross study single institution subgroup analysis that may not reflect the complete trial data. The overall incidence of infection was similar to what has previously been reported in patients receiving CD-19 directed CAR T-cell therapy, even with persistent neutropenia after one month documented in 41% of patients.